1. Field of Invention
The present invention is directed to hexahydroindenopyridine compounds which act as spermicides and/or antifungals, spermicidal or antifungal compositions containing the same, and methods for killing motile sperm or fungi using the compounds and compositions.
2. Discussion of the Background
In the US and much of the Western world, the high and growing demand for contraceptives is a function of lifestyle preferences, while in many developing nations, population control is a highly pressing public health concern. Considering that contraception is a global health need, albeit for different reasons in different parts of the world, the total market for a male contraceptive could be much larger than that accounted for in the US figures alone.
In the Western World, the market for contraceptives has changed relatively little over the past 50 years, with “the pill” having been developed in 1951 and remaining unparalleled as the popular choice for contraception. Advances in contraception research have only offered a few more choices, all to women, who have historically born the brunt of the responsibility, cost, and health-risk (in particular, risks of cardiovascular disease and certain types of cancer associated with long-term use of hormonal-based contraceptives) of contraception. The condom, invented in the 16th century, is the only significant form of contraception available to men (other than “withdrawal” and vasectomy). The only real innovative improvement that has occurred with the condom came with the vulcanization of rubber in the 19th century.1 1 From New Scientist, 20 Apr. 1994, Vol 142 No 1923.
As pharmaceutical companies develop compounds for sexual dysfunction (e.g., Viagra for erectile dysfunction), the demand for contraceptives is expected to grow. Condom sales in the U.S. rose 5.8% during 1999, generating $260 million in revenue, reflecting what some have called a new American sexual revolution.2 Although the majority of women of child-bearing age already practice contraception3, still half of all pregnancies are unintended.4 There has been a persistent appeal from health and consumer groups for more alternatives, in particular for alternatives that allow men to assume a greater portion of contraceptive responsibility. Global concerns have led organizations such as the World Health Organization and Family Health International to launch initiatives aimed at encouraging the development of male contraceptives. At least two companies, Schering and Organon, are investing heavily to bring a hormonal male contraceptive to market within this decade. 2 Drug Store News, Nov. 29, 1999 v21 il9 p29.3 58% of all married women in the world of reproductive age use some sort of contraceptive method (The Population Division of the United Nations Department of Economic and Social Affairs 2000).4 NICHD, Contraception and Reproductive Health Branch: Report to the NACHHD Council September 1999.
Safe and effective orally active male contraceptive drugs have been sought for many years. However, the development of a drug which can safely interrupt spermatogenesis without affecting libido and thereby function as a male contraceptive agent has proven to be a difficult task.
An ideal contraceptive for the male would be one that effectively arrests the production of spermatozoa, blocks their fertilizing capacity without affecting libido or accessory sex organs and their functions, and/or kills motile spermatozoa. In addition it should have a wide separation of effective and toxic doses, and the method should be reversible. Such an ideal male contraceptive agent is currently unavailable.
Some general cellular toxicants such as anticancer agents and alkylating agents affect spermatogenesis, but are obviously not acceptable as contraceptives. Compounds which interfere with cellular energy processes, such as thiosugars also interfere with spermatogenesis, are not sufficiently selective. Androgens such as testosterone and its analogs, when given in sufficiently high doses, interfere with spermatogenesis, probably through a mechanism involving the hypothalamic-pituitary axis. These steroid compounds have been used successfully in clinical studies. However, the anabolic properties of these steroids may give rise to undesirable side effects.
Gonadotrophin releasing hormone (GNRH) analogs have been actively investigated as compounds which effectively block spermatogenesis. However, GNRH analogs interfere with endogenous testosterone production and thus decrease libido unless supplementary androgens are administered.
One approach to male contraceptives is based on identification and exploitation of the biochemistry of the male reproductive process. The testis consists of three functional compartments. The first, responsible for the production of sperm, consists of seminiferous tubules which contain developing germ cells. The second is the Sertoli cell, also located inside the seminiferous tubule, which contributes to the organizational and functional coordination of the spermatogenic process and probably has paracrine and autocrine roles. Due to the complex organizational relationship between the Sertoli cell and the developing germ cells, and the presence of tight junctions between neighboring Sertoli cells, a blood testis barrier is formed, dividing the seminiferous tubule into areas that are isolated from the direct access by blood-borne chemicals or nutrients. Surrounding the tubules, in the interstitial tissue, are Leydig cells that have several endocrine and paracrine functions, the production of testosterone being the best described.
The germinal cells divide and differentiate progressively, moving as they mature from the basement membrane to the tubule lumen. Spermatogonia lie in the basal compartment, and selectively recruited spermatogonia divide mitotically to become either cells that persist as spermatogonia or differentiate into primary spermatocytes. The primary spermatocytes migrate through the junctions between the Sertoli cells and divide meiotically to form secondary spermatocytes. Secondary spermatocytes divide to form spermatids. The spermatids then differentiate into mature spermatozoa. Differentiation of the spermatids is often termed spermatogenesis. However, for the purposes of this application, “spermatogenesis” is defined to cover the entire process of formation and maturation (differentiation) of sperm and an “antispermatogenic compound” is one which disrupts any part of this process.
A summary of Sertoli cell functions is as follows: (a) support and nutrition to the seminiferous epithelium, (b) release of late spermatids into the tubule lumen, (c) formation of a morphological and physiologic blood testes barrier, (d) phagocytosis of degenerating germ cells, and (e) regulation of the cycle of seminiferous epithelium.
The Leydig cell also supports spermatogenesis. Luteinizing hormone (LH) from the pituitary stimulates testosterone production by the Leydig cell. Testosterone and its metabolite, dihydrotestosterone, are necessary to support normal spermatogenesis. Testosterone receptors are present on various germ cell types. Testosterone is delivered through the blood testis barrier, likely through transport into the Sertoli cell, where it is metabolized into estradiol, dihydrotestosterone, or remains unaltered.
Some, if not all of the germ cell types, interact with the Leydig and/or Sertoli cell. These interactions are in the form of chemical messengers that are produced by Sertoli, Leydig, and germ cell(s). For example, the pachytene spermatocyte modulates the secretion of a Sertoli cell proteinaceous factor that in turn stimulates steroidogenesis by the Leydig cell. The binding of spermatids occurs only to Sertoli cells which are rendered competent or functional by exposure to FSH. The Sertoli cell of rats secretes several proteins in a cyclic fashion, with maximal production occurring at a specific stage of the seminiferous epithelium; that is, when it is in association with a specific group of germ cells. Clusterin is produced maximally by Sertoli cells when the seminiferous epithelium is in a Stage VII or VII configuration that is independent of FSH stimulation, suggesting a local regulation of Sertoli secretory function by germ cells.
Hexahydroindenopyridine compound no. 20-438 developed by Sandoz, Ltd. (compound 1 in FIG. 1) has been shown to provide reversible inhibition of spermatogenesis on oral administration to animals. See Arch. Toxicol. Suppl., 1984, 7:171-173; Arch. Toxicol. Suppl., 1978, 1:323-326; and Mutation Research, 1979, 66:113-127.
The synthesis of a variety of indenopyridine compounds as racemic mixtures is known and described, for example, in U.S. Pat. Nos. 2,470,108; 2,470,109; 2,546,652; 3,627,773; 3,678,057; 3,462,443; 3,408,353; 3,497,517; 3,574,686; 3,678,058 and 3,991,066. These indenopyridine compounds have a variety of uses including use as serotonin antagonists exhibiting antiphlogistic and analgesic properties, hematoblast aggregation inhibitors, sedatives, and neuroleptic compounds as well as ulcer-protective, hypotensive and anorexigenic compounds.
U.S. Pat. Nos. 5,319,084 and 5,952,336 disclose hexahydroindenopyridine compounds having antispermatogenic activity in which the 5-position is substituted with a phenyl ring having a para-position substituent.
Despite extensive research in this field, a need continues to exist for active reversible male antifertility drugs which have limited side-effects. A continuing problem is the need to administer known compounds at dosage levels which may cause side-effects. An additional problem in this field is the lack of suitable imaging agents having specific binding sites on or in the testes. A need continues to exist for compounds which may be used as imaging agents in the study of testicular function and in the diagnosis of testicular malfunction.
In addition to male oral contraceptives, there is a need for more effective spermicidal compositions for use as traditional topical/external contraception practices.